Severe mitral regurgitation due to mitral valve prolapse: risk factors for development, progression, and need for mitral valve surgery.

Patients with mitral valve prolapse (MVP) may develop severe mitral regurgitation (MR) and require valve surgery. Preliminary data suggest that high body weight and blood pressure might add to the irreversible factors of older age and male gender in increasing risk of these complications. Fifty-four patients with severe MR due to MVP were compared with 117 control subjects with uncomplicated MVP to elucidate factors independently associated with severe MR: the need for valve surgery and the cumulative risk of requiring mitral valve surgery. Patients with severe MR were older (p<0.00005), more overweight (p = 0.002), had higher systolic (p = 0.0003) and diastolic (p = 0.007) blood pressures, and were more likely to have hypertension (p = 0.0001) and to be men (p<0.001). In both groups, men had higher blood pressure and relative body weight than women. In multivariate analysis, older age was most strongly associated with MR; higher body mass index, hypertension, and gender were independent predictors of severe MR in analyses that excluded age. Among the 54 patients with severe MR, the 32 (59%) who underwent mitral valve surgery during 11 years of follow-up were older, more overweight, and more likely to be hypertensive than those not requiring surgery. Among patients undergoing mitral valve surgery in 3 centers, mitral prolapse was the etiology in 25%, 67% of whom were men. Using these data and national statistics, we estimate that the gender-specific cumulative risk for requiring valvular surgery for severe MR in subjects with MVP is 0.8% in women and 2.6% in men before age 65, and 1.4% and 5.5% by age 75. Thus, subjects with MVP who are older, more overweight, and hypertensive are at greater risk for severe MR and valve surgery. Higher blood pressure and relative weight in men with MVP appear to contribute to the gender difference in risk for severe MR.

Preoperative predictors of late postoperative outcome among patients with nonischemic mitral regurgitation with 'high risk' descriptors and comparison with unoperated patients.

Among patients with chronic nonischemic mitral regurgitation (MR), high short-term mortality risk can be identified by left (LV) and/or right ventricular (RV) ejection fraction (EF) criteria (LVEF 20%, MVR significantly improved survival versus medical treatment (rest: p < 0.0001, exercise: p = 0.0003). In high risk MR patients, MVR improves survival; preoperative RV performance can define subgroups with different long-term postoperative survival.

Prognostication in 3-vessel coronary artery disease based on left ventricular ejection fraction during exercise : influence of coronary artery bypass grafting.

BACKGROUND: Previous data indicate that left ventricular ejection fraction (LVEF) provides prognostic information among patients with coronary artery disease (CAD), but the value of such testing specifically for defining benefits of coronary artery bypass grafting (CABG) may relate to severity of exercise-inducible ischemia measured noninvasively before surgery. METHODS AND RESULTS: To determine the independent prognostic importance of preoperative ischemia severity for predicting outcomes of CABG among patients with extensive CAD, we monitored 167 stable patients with angiographically documented 3-vessel CAD (average follow-up of 9 years in event-free patients) who previously had undergone rest and exercise radionuclide cineangiography. Their course was correlated with data obtained during initial radionuclide testing, coronary arteriography, and clinical evaluation at study entry. Fifty-two patients received medical treatment only, and 115 underwent CABG (44 early [

Prediction of indications for valve replacement among asymptomatic or minimally symptomatic patients with chronic aortic regurgitation and normal left ventricular performance.

BACKGROUND: Optimal criteria for valve replacement are unclear in asymptomatic/minimally symptomatic patients with aortic regurgitation (AR) and normal left ventricular (LV) performance at rest. Moreover, previous studies have not assessed the prognostic capacity of load-adjusted LV performance ("contractility") variables, which may be fundamentally related to clinical state. Therefore, 18 years ago, we set out to test prospectively the hypothesis that objective noninvasive measures of LV size and performance and, specifically, of load-adjusted variables, assessed at rest and during exercise (ex), could predict the development of currently accepted indications for operation for AR. METHODS AND RESULTS: Clinical variables and measures of LV size, performance, and end-systolic wall stress (ESS) were assessed annually in 104 patients by radionuclide cineangiography at rest and maximal ex and by echocardiography at rest; ESS was derived during ex. During an average 7.3-year follow-up among patients who had not been operated on, 39 of 104 patients either died suddenly (n = 4) or developed operable symptoms only (n = 22) or subnormal LV performance with or without symptoms (n = 13) (progression rate=6.2%/y). By multivariate Cox model analysis, change (delta) in LV ejection fraction (EF) from rest to ex, normalized for deltaESS from rest to ex (deltaLVEF-deltaESS index), was the strongest predictor of progression to any end point or to sudden cardiac death alone. Unadjusted deltaLVEF was almost as efficient. Symptom status modified prediction on the basis of the deltaLVEF-deltaESS index. The population tercile at highest risk by deltaLVEF-deltaESS progressed to end points at a rate of 13.3%/y, and the lowest-risk tercile progressed at 1.8%/y. CONCLUSIONS: Currently accepted symptom and LV performance indications for valve replacement, as well as sudden cardiac death, can be predicted in asymptomatic/minimally symptomatic patients with AR by load-adjusted deltaLVEF-deltaESS index, which includes data obtained during exercise.

Relation of ultra-low frequency heart rate variability to the clinical course of chronic aortic regurgitation.

We examined the relation of the standard deviation of the 5-minute mean RR intervals over 24 hours (SDANN), a measure of ultra-low frequency heart rate variability (HRV) (<0.0033 Hz), and other measures of HRV to clinical outcome events in 50 asymptomatic or minimally symptomatic patients with chronic severe aortic regurgitation (AR) who underwent ambulatory electrocardiography as part of a prospective study of the natural history of regurgitant valvular diseases. At entry, all patients were in sinus rhythm and had New York Heart Association functional class I or minimal II congestive heart failure, with left ventricular (LV) ejection fraction > or = 45% and LV end-diastolic dimension > or = 5.5 cm in women and > or = 5.9 cm in men. End points were defined as progression to aortic valve replacement (n = 19) or sudden cardiac death (n = 1) during the mean follow-up period of 8.1 +/- 3.8 years. With the median SDANN of 145 ms as a partition value, the average annual risk of end-point events in patients with low SDANN was significantly greater than the event rate in patients with high SDANN (11%/year vs 2%/year, p <0.0003). In multivariate analysis, reduced SDANN was associated with end-point events independent of LV function, LV end-systolic dimension, and symptom status (p = 0.001). We conclude that reduced ultra-low frequency HRV measured as SDANN is strongly related to progression to valve surgery in asymptomatic and minimally symptomatic patients with chronic AR.

Combined rest and exercise electrocardiographic repolarization findings in relation to structural and functional abnormalities in asymptomatic aortic regurgitation.

The relationship of combined rest and exercise electrocardiographic (ECG) repolarization abnormalities to left ventricular geometry and function was examined in 48 patients with asymptomatic chronic pure aortic regurgitation and no recent use of digitalis. Echocardiographic and radionuclide cineangiographic findings were compared in groups defined by the presence or absence of the "strain" pattern of repolarization abnormality on the resting ECG and also by the presence or absence of standard positive repolarization changes during upright treadmill exercise ( > 0.1 mV additional horizontal or downsloping ST depression). These hierarchic groups demonstrated trends toward progressively abnormal left ventricular dimensions, mass, wall stress, and change in ejection fraction with exercise. Although the presence of the strain pattern on the resting ECG alone was most strongly correlated with underlying functional and geometric abnormalities, an abnormal exercise test response was independently associated with abnormal left ventricular systolic dimension. The large group of patients with no symptoms and normal resting repolarization had only 0% to 4% prevalences of markedly increased systolic dimension (> 55 mm), reduced ejection fraction at rest (< 45%), or reduced ejection fraction during exercise (< 40%), whereas the small group of patients with abnormal resting repolarization and a positive exercise test response had 50% to 83% prevalences of these findings. These data suggest a possible role for rest and exercise ECG in the serial evaluation of patients with aortic regurgitation.

Variability of the ventricular response in atrial fibrillation and prognosis in chronic nonischemic mitral regurgitation.

Although reduced heart rate (HR) variability during sinus rhythm is associated with an adverse prognosis in a variety of clinical settings, the significance of measures of variability of the ventricular response in atrial fibrillation (AF) requires clarification. AF is common among patients with chronic severe mitral regurgitation (MR) and potentially limits the application of HR variability techniques in this population. Therefore, this study examined the physiologic correlates and prognostic significance of measures of HR variability in 21 patients with nonischemic causes of chronic severe MR who had chronic AF and underwent 24-hour ambulatory electrocardiography as part of a prospective study of the natural history of regurgitant valvular heart disease. Patients were followed for up to 9.1 years and end points of mortality and progression to mitral valve surgery were tabulated. Time- and frequency-domain measurements of high-, low-, and ultra-low-frequency HR variability were computed and compared with resting ventricular function by radionuclide cineangiography and outcome. All measures of HR variability were covariate (pair-wise r values between 0.48 and 0.99, all p values < 0.03), and none of the variables was significantly related to age, ventricular premature complex (VPC) density, or right or left ventricular ejection fraction. Reductions in time-domain measurements of ultra-low- and high-frequency HR variability were significant predictors of the combined risk of mortality or requirement for mitral valve surgery (p = 0.02 and p = 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Right and left ventricular performance 10 years after Mustard repair of transposition of the great arteries.

Twenty-two late survivors of Mustard repair of transposition of the great arteries underwent treadmill exercise testing to assess exercise endurance, and radionuclide cineangiography to measure rest and exercise right ventricular (RV) and left ventricular (LV) ejection fraction (EF). Mean age at Mustard repair was 1.8 +/- 2.4 years and at initial exercise study 14.1 +/- 4.5 years. All patients were asymptomatic at study entry. Treadmill endurance time (9 to 12 minutes) was within the normal range for age in 18 of 20 patients. LVEF and RVEF at rest were within normal limits (55 +/- 8% and 52 +/- 9%, respectively). All LVEFs and RVEFs during exercise were also within the normal range (64 +/- 8% and 57 +/- 9%, respectively). However, the magnitude of increase in EF (rest to exercise) was subnormal for the right ventricle in 7 patients and for the left ventricle in 2 patients. Exercise RVEF was higher in patients with simple transposition who underwent repair at < 1 year of age than in those who underwent operation at age > 1 year (62 +/- 10% vs 52 +/- 7%). Serial study in 6 patients revealed no change in average RVEF or LVEF after an average interval of 4.4 years. One patient with complex transposition subsequently developed refractory congestive heart failure requiring cardiac transplantation. It is concluded that exercise endurance and LVEF and RVEF at rest and exercise are generally well preserved up to 19 years after Mustard repair, particularly in cases of simple transposition of the great arteries repaired before 1 year of age.

Natural history of the asymptomatic/minimally symptomatic patient with severe mitral regurgitation secondary to mitral valve prolapse and normal right and left ventricular performance.

The natural history of patients with severe nonischemic mitral regurgitation (MR) from mitral valve prolapse, who are asymptomatic or minimally symptomatic and have normal right ventricular (RV) and left ventricular (LV) performance, has not been evaluated previously. To define natural history in this population and to determine if any objective variables could predict disease progression, 31 patients were followed annually with severe MR due to prolapse, who at entry were asymptomatic or minimally symptomatic and had normal RV and LV performance at rest by radionuclide cineangiography. Average follow-up in patients not reaching surgical end point was 4.7 years. The Kaplan-Meier product limit estimates were used to determine the rate of progression to either "operable" symptoms or to previously defined "high risk" ventricular performance descriptors, if the latter occurred first. Univariate comparisons of Kaplan-Meier curves and multivariate Cox proportional hazards analyses were used to define prognostically important variables measured at entry. Fourteen patients developed symptoms warranting referral for operation; none developed high-risk ventricular performance descriptors. The annual end point risk was 10.3%. Of all covariates, only change in RV ejection fraction from rest to exercise was significantly associated with disease progression. Annual risk of progression to surgical end point was 4.9% in the subgroup in which this parameter increased with exercise and 14.7% in the subgroup without an increase (p = 0.04). Patients with severe MR due to mitral valve prolapse, who are asymptomatic or minimally symptomatic with normal ventricular performance, can be expected to progress to surgical indications at an annual rate of 10.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic value and physiological correlates of heart rate variability in chronic severe mitral regurgitation.

BACKGROUND: A variety of measures of heart rate variability have been devised to measure high-frequency (0.15-0.40 Hz), low-frequency (0.04-0.15 Hz), or ultralow-frequency (< 0.0033 Hz) fluctuations in sinus cycle length. Although measures of low-frequency and ultralow-frequency heart rate variability have been shown to correlate with prognosis in several populations with ischemic heart disease, their relevance to patients with primary valvular heart disease remains to be determined. METHODS AND RESULTS: Thirty-eight patients with nonischemic causes of chronic severe mitral regurgitation who were in sinus rhythm underwent 24-hour ambulatory electrocardiography as part of a prospective study of the natural history of regurgitant valvular heart disease. Patients were followed for as long as 9.2 years, and end points of mortality, progression to mitral valve surgery, and development of chronic atrial fibrillation were tabulated. Time- and frequency-domain measurements of high-frequency, low-frequency, and ultralow-frequency heart rate variability were computed and compared with resting ventricular function by radionuclide cineangiography and outcome. The standard deviation of the 5-minute mean RR intervals (SDANN), a measure of ultralow-frequency heart rate variability, was correlated with left ventricular ejection fraction (r = 0.49, p = 0.002) and right ventricular ejection fraction (r = 0.43, p = 0.007), whereas low-frequency and high-frequency heart rate variabilities were not. Heart rate, ultralow-frequency heart rate variability, and, to a lesser extent, high-frequency heart rate variability exhibited significant diurnal variation, but low-frequency heart rate variability did not. Heart rate and ultralow-frequency, low-frequency, and combined low- and high-frequency heart rate variability predicted mortality and total events. The most powerful predictor of subsequent events was SDANN: Patients with reduced SDANN were significantly more likely to develop end-point events (p < 0.001) with increased progression to mitral valve surgery (p < 0.001) as well as increased early mortality (p = 0.02). In a multivariate proportional hazards model, SDANN retained independent predictive power (p = 0.001). Likewise, SDANN was the only variable that was significantly associated with the subsequent development of atrial fibrillation (relative risk, 3.1; p = 0.03). CONCLUSIONS: Ultralow-frequency heart rate variability, as measured by SDANN, correlates with right and left ventricular performance and predicts development of atrial fibrillation, mortality, and progression to valve surgery in patients with chronic severe mitral regurgitation.

Natural history of left ventricular performance at rest and during exercise after aortic valve replacement for aortic regurgitation.

Previous studies of left ventricular performance in aortic regurgitation uniformly indicate improvement within the year after aortic valve replacement but differ regarding the likelihood of additional later improvement. To resolve this difference, to more precisely define the pattern of postoperative left ventricular performance variation, and to assess the impact of valve replacement on ejection fraction during exercise, we evaluated radionuclide cineangiograms obtained annually or nearly annually for approximately 5 years in 21 prospectively studied patients who had undergone valve replacement for aortic regurgitation. Ejection fraction rose from less than 8 months before operation to 5-11 (average 7) months after operation and continued to rise for 1 additional year (rest) and 2 additional years (exercise) before reaching a stable plateau until the final study 54-72 (average 63) months postoperatively. Mean ejection fractions at rest were 45% preoperatively, 50% less than 1 year postoperatively (p = 0.12), 54% at year 1-2 (p = 0.01 versus less than 1 year), 56% at year 2-3 (NS versus year 1-2) and year 4-6 (NS versus year 1-2 or 2-3), and during exercise were 39% preoperatively, 49% less than 1 year postoperatively (p less than 0.01), 54% at year 1-2 (p less than 0.01 versus less than 1 year, NS versus year 2-3, p less than 0.05 versus year 4-6), 60% at year 2-3, and 61% at year 4-6 (NS versus year 2-3). Late improvement was found most consistently among patients with relatively depressed performance before operation.(ABSTRACT TRUNCATED AT 250 WORDS)

Right ventricular function in severe non-ischaemic mitral insufficiency.

Mitral insufficiency (regurgitation) is a disease of both ventricles. To determine the pathophysiological implications and clinical value of assessment of right ventricular function in this disease, right ventricular ejection fraction was determined by radionuclide cineangiography (r = 0.73, P less than 0.01, vs contrast angiography, n = 30) in patients with severe, non-ischaemic mitral regurgitation. Among 31 patients with isolated mitral regurgitation treated medically, five died, all within 2 years of follow-up; all five were among the eight patients with left ventricular ejection fraction less than or equal to 45% (lower limit of normal), and among the six patients with right ventricular ejection fraction less than or equal to 30% (almost invariably associated with at least mild pulmonary hypertension). During the same period, valve replacement was performed in 22 patients with isolated mitral regurgitation; among the six patients with right ventricular ejection fraction less than or equal to 30% before operation, only one died (P less than 0.05), indicating the risk-mitigating effect of valve replacement. Among eight pre-operative patients with combined mitral and aortic regurgitation, four died within 7 years after double valve replacement; all patients with right ventricular ejection fraction during exercise less than 20% died. After mitral valve replacement for isolated mitral regurgitation, right ventricular ejection fraction improved rapidly (average 8% in less than 1 year (P less than 0.05); 3% more at 3 years after operation (P less than 0.05)). Post-operative symptom persistence was predictable from ventricular ejection fraction before operation less than 30% (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Preoperative left and right ventricular performance in combined aortic and mitral regurgitation and comparison with isolated aortic or mitral regurgitation.

Left and right ventricular performance characteristics in operative candidates with combined aortic and mitral regurgitation (AR/MR) have not been well defined. Therefore, we determined radionuclide cineangiographic ejection fractions, as well as echocardiographic and hemodynamic parameters, in 8 symptomatic patients undergoing double-valve replacement with pure, severe AR/MR. In order to gain insight into the basis for the poor postoperative survival in patients with this intrinsically biventricular disease, we compared these results with those of 29 symptomatic patients with isolated AR and with 18 symptomatic patients with isolated MR, all also undergoing valve replacement. Before operation, patients with AR/MR had significantly lower left ventricular (LV) ejection fraction than patients with MR (rest, 40 +/- 9% vs 52 +/- 10%, p less than 0.025; exercise, 35 +/- 12% vs 54 +/- 12%, p less than 0.005) and tended to have lower LV ejection fraction than patients with AR alone (rest, 40 +/- 9% vs 45 +/- 12%, difference not significant; exercise, 35 +/- 12% vs 39 +/- 11%, difference not significant); right ventricular (RV) ejection fraction was lower in AR/MR than in AR (p less than 0.01), and tended to be lower than in MR (difference not significant). At average postoperative follow-up of 72 to 76 months (survivors in each group), symptomatic patients with AR/MR had significantly poorer survival than symptomatic patients with isolated MR (p less than 0.05) and were more likely to have persistent symptoms than patients with AR (p less than 0.05). These findings suggest that symptomatic patients with AR/MR have poorer LV and RV performance than similarly symptomatic operative candidates with AR or MR alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of atrial natriuretic factor to left ventricular volume and mass.

Although atrial natriuretic factor is primarily of atrial origin, recent observations indicate that the hormone is also synthesized by hypertrophied left ventricular myocardium. To assess the separate influences of left ventricular and left atrial dilatation and left ventricular hypertrophy on human atrial natriuretic factor levels, left atrial dimension and volume and left ventricular dimension and mass were compared in 49 normal subjects, in 33 patients with chronic aortic regurgitation, and in 15 patients with chronic mitral regurgitation. When compared with normal subjects, patients with chronic aortic and mitral regurgitation had similarly dilated and hypertrophied left ventricles (p less than 0.0005), while only mitral regurgitation patients had significantly enlarged (p less than 0.0005) mean left atrial dimension and volume. Likewise, plasma atrial natriuretic factor was elevated among patients with mitral regurgitation (60.3 +/- 47.0 fmol/ml) but was normal in patients with aortic regurgitation (19.0 +/- 11.0 fmol/ml versus 12.4 +/- 5.2 fmol/ml in normals; both p less than 0.0005 versus mitral regurgitation). Among all 97 subjects, atrial natriuretic factor levels correlated more closely with left atrial dimension and volume (r = 0.62 and 0.64, p less than 0.0005) than with left ventricular dimension (r = 0.44, p less than 0.0005) or mass (r = 0.40, p less than 0.0005). In addition, multivariate analysis indicated that left atrial volume bore a stronger independent relationship to plasma atrial natriuretic factor levels than either age or left ventricular variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of left ventricular dilatation, hypertrophy, and dysfunction by valve replacement in aortic regurgitation.

Although aortic valve replacement for aortic regurgitation relieves left ventricular volume overload, ventricular geometry does not consistently normalize. To assess the extent, determinants, and functional consequences of reversal of left ventricular dilatation and hypertrophy, 38 patients with severe aortic regurgitation were studied pre- and postoperatively by serial echocardiography and radionuclide cineangiography. Left ventricular end-diastolic dimension normalized in 58% of patients by 9 +/- 6 months postoperatively, at which time 50% of patients had normalized mass; cumulative normalization rose to 66% for end-diastolic dimension and 68% for left ventricular mass during further follow-up. All patients who had normalized end-diastolic dimension also had normal postoperative ejection fractions (mean 61 +/- 8%). In contrast, patients in whom the left ventricle remained dilated had a 42% prevalence of subnormal postoperative left ventricular ejection fraction. Preoperative left ventricular end-systolic dimension less than or equal to 55 mm identified 86% of patients in whom end-diastolic dimension normalized, whereas end-systolic dimension exceeded 55 mm in 81% of those with persistent dilatation; other proposed preoperative predictors of operative outcome correctly identified lower proportions (from 59% to 71%) of patients in whom left ventricular size did or did not normalize. In conclusion, aortic valve replacement resulted in normalized left ventricular chamber size and mass in two thirds of the patients selected for operation by current criteria; favorable geometric outcome is associated with persistence or recovery of normal left ventricular function.

Comparison of mitral valve dimensions and motion in mitral valve prolapse with severe mitral regurgitation to uncomplicated mitral valve prolapse and to mitral regurgitation without mitral valve prolapse.

To determine the mitral valve abnormalities associated with hemodynamically important mitral regurgitation (MR) among patients with mitral valve prolapse (MVP), computerized 2-dimensional echocardiographic measurements of mitral leaflet and anular dimensions and motion in 26 patients with MVP and MR were compared to those in 48 subjects with uncomplicated MVP, 16 patients with MR due to etiologies other than MVP (rheumatic in 8) and 35 normal adults. Compared to both uncomplicated MVP and normal subjects, patients with MVP plus MR were older (p less than 0.05), had strikingly large mitral leaflets and anulus (p less than 0.0005) and were more likely to have systolic billowing of mitral leaflets in the parasternal long-axis view (24 of 26 [92%] vs 24 of 48 subjects with uncomplicated MVP [50%], p less than 0.001). Overlap in anular and posterior leaflet dimensions in normal and uncomplicated MVP subjects occurred in the 20 MVP plus MR patients who continue to be followed medically but not in the 6 MVP plus MR patients who underwent mitral valve surgery during 22 +/- 14 months follow-up. Patients with MR due to rheumatic or other non-MVP etiologies had enlargement of mitral leaflets and anulus virtually identical to that in MVP plus MR patients. In conclusion, patients with severe MR due to MVP are older, have striking mitral valve enlargement and more frequently exhibit leaflet billowing compared with subjects with uncomplicated MVP. Similar mitral leaflet enlargement was found in patients with non-MVP etiologies of MR, suggesting that mitral anular and leaflet enlargement may play a more general role in the pathogenesis of MR than is currently appreciated.